Synthesis of compounds of the ascorbic acid series



Patented June 15, 1948 umrso STATES PATENT orncs syn-masts or COMPOUNDS or me liscorusro ACID seams Wilhelm Wenner, Montclair, N. J.,- assig'nor to Hoifmann-La Roche Inc., a corporation of New Jersey No Drawing. Application October 27, 1045, Serial No. 025,109

OAlkyl C O 0 H02. 1 cnou --i 801% HOE H ($8010., (2780B)- JJHiR HsR in which n represents zero (0) or a low integer, "alkyP represents methyl, ethyl, or the like, and R stands for H or OH.

The formulae I and II are generic in their characterization, no specific stereochemical configuration being designated. The general conversion is represented above with a broken lin below the No. 4 carbon atom, since the synthesis of this application is particularly associated with the lactonization brought about in that part of the ester (1) above the broken line. It will be apparent, therefore, that, since 11 may be zero or an integer, esters of keto-pentonic acids, esters of keto-hexonic acids, and esters of keto-heptonic acids, may be subjected to my novel transformation.

It is of particular significance that my novel conversion may be employed not only for the treatment of isolated esters, but also for the transformation of esters as they are present in the reaction mixtures in which they are made.

Typical and important examples of keto-acids which may be esterifledand treated by my novel process are Z-keto-d-glueonicacid (III) and 2- keto-l-gulonic acid (IV).

coon coon e0 0 noon no a n on n on n on no a Esters of z-keto-d-gluconic acid (III), e. g., methyl ester or ethyl ester, yield d-isoascorbic acid compounds (V), also known as d-arabo 20 Claims. (Cl- 260-3445) ascorbic acid, whereas esters oi z-keto-gulonie acid (IV), produce l-ascorbic acid (VI); also I known as vitamin C.

The formulae d-isoascorbic acid and l-ascorbic acid are reproduced, respectively, as (V) and CO 00 no i not 1 HOC| H00 Ht Ht H OH HO H CHsOH (EHQOH 2-keto-6-desoxy-l-gulonic acid ester (VIII) is converted into the physiologically active B-desoxy- 'l-ascorbic acid VIII) as represented by:

C0 OAlkyl C0 0 to?!) E0471! 0 a0 H OH EC -B0 H HOJEH Hr H;

(VII) (VIII) The general process of lactonization to convert, e. g., 2-keto-l-gu1onic acid into ascorbic acid, is known in the art. Such lactonization has been carried out by heating the free acid in neutral, acid, or alkaline solution or by heating esters oi the keto-acid with sodium alkoxides, sodium acetate, calcium carbonate, or the like. Maurer (Ber. 1941, 74, 1003, 1006) has reported a conversion (determined by titration only) by the use of water miscible diethyl amine. Tertiary amines have also been employed as conversion agents (U. S. P. No. 2,160,621). v

I have found that certain secondary amines are of particular value for effecting the lectonization of alkyl esters of the keto-acids described above. These secmdary amines are characterized by relatively strong basicity and relatively low solubility in water. Specific examples of suitable secondary amines are dicyclohexylamine, N-methyl-cyclohexylamine, N-ethyl cyclohexylamine, N propyl cyclohexylamine, and N- methyl-benzylamine. Other strongly basic, relatively water-insoluble secondary amines can also be employed.

At least one molecular equivalent of the amine u must be employed for each mole of the ester.

- (NIOH) 3 The temperature is preferably maintained at about 6040 C.

It may be pointed out that in the course or the lactonization oi the keto-acid esters. the amine used for the conversion forms a salt of the resulting lactonized acid, e. 8.. of d-isoascorbic acid or oil l-ascorbic acid. Thus the treatment of methyl-Z-keto-d-gluconate with dicyclohexylamine, produces dicyclohexylamine-d-isoascorbate. By treatment ot'the amine salt with an alkaline agent, e. g., sodium hydroxide, sodiumd-isoascorbate is formed. The conversion into the free acid, e. g., d-isoascorbic acid. is carried out by acidification with, e. g.. hydrochloric acid. It will be apparent, therefore, that the general course of reaction, may be represented as tolows:

(amine) Kate-acid ester Amino salt oi the ascorbic acid (H01) Na salt of the ascorbic acid --0 The significance of the invention will be made apparent by the following illustrative examples, which will serve as a guide for those skilled in tbeasoorbicacld the art to carry out the transformation. It will be apparent from these examples that the esters may be treated in isolated condition, or in the non-isolated form. The latter modification is 01' particular value-from a commercial viewpoint.

' skilled in the art in the light of theguiding principles disclosed herein.

Example 1 104 parts of 2-keto-l-gu1onic acid methylester. 800 parts of absolute alcohol, and 91 parts of dicyclohexylamine are stirred and heated for 1 to 1% hours in a waterbath kept at 70. After this time a sample titrated with iodine solution after acidification shows a rate of conversion oi Example 3 146 parts of diacetone-Z -keto-l-guIOnic acid are refluxed with 1200 parts of methanol and 22 parts of 18% conc. hydrochloric acid for 10 hours. Aiter cooling 1200 parts oi benzene are added. The mixture is concentrated to a volume of about 200 cc. To this solution are added 800 parts of methanol and 95 parts oi dicyclohexylamine. The mixture is stirred and heated for 2 hours to (lo-85. Aiter cooling a solution of 21 parts of sodium hydroxide in 200 parts oi 95% methanol is slowly added. Sodium l-ascorbate separates. It is filtered alter cooling overnight and dried at a temperature not exceeding 30 in a vacuum. 1

' Example 4 then titrated with 0.1 n-iodine solution. The

conversion is finished after about 1% hours. After cooling, 20 cc. of water are added. The mixture is cooled and a solution of 4.4 grams of sodium hydroxide in 20 cc. of water is slowly added with stirring. Sodium d-isoascorbate pre- 40 cipitates. It is filtered. washed with some ice 90-100%. The mixture is cooled to room-temperature. A solution of 21 parts oi sodium hydroxide in 220 parts of 95% alcohol is added slowly. Sodium l-ascorbate precipitates in small crystals. It is filtered, washed with 350 parts of alcohol and dried at room-temperature in a vacuum drier. This sodium salt is converted into the free l-ascorblc acid by known methods, e. g., by stirring the crude salt in alcohol and addin the calculated amount of alcoholic hydrochloric acid, filtering the solution from the sodium chloride, and evaporating the filtrate.

Example 2 104 parts of 98% sulfuric acid is mixed with 3000 parts of anhydrous alcohol. 472 parts of technical'calcium 2-keto-d-gluconate are added. The agitated mixture is heated under strong refiuxior 4 hours. Heating is then discontinued. and the mixture stirred over night. 433 parts of dicyclohexylamine areadded and the mixture is heated to 58 to 60 with stirring. Samples are withdrawn in intervals and, alter dilution with water and acidification. are titrated. when no more increase in iodine titration is noted, the solution is cooled. It is filtered from. the calcium sulfate. The latter is washed with alcohol and with water. The main filtrate and the washes are combined. with stirring. a solution cold ethanol, and dried.

Example 5 58 grams of diacetone-Z-keto-l-gulonic acid.

340 cc. of absolute ethanol, and 4 cc. of aqueous concentrated hydrochloric acid are refluxed for eight hours.

stirred and heated to 60-70" for 2 hours. After cooling, a solution of 10 grams sodium hydroxide in cc. of 95% ethanol is slowly added with stirring. Sodium l-ascorbate crystallizes and is isolated by filtration.

Example 6 20.8 grams methyl-Z-keto-gulonate cc. absolute ethanol, and 13 grams oiN-ethyl-cyclohexylamine are stirred for 1% hours at 70. Aiter cooling. 4.2 grams sodium hydroxide dissolved in 55 cc. of 95% ethanol are added slowly. Sodium-l-ascorbate crystallizes and is isolated by filtration.

Example 7 To the cooled solution are added .45 grams of dicyclohexylamine. The mixture is 5 Example 8 Example 9 20.8 grams of methyl-2-ketogulonate. 160 cc. of absolute ethanol, and 12.4 grams of N-methylbenzylamine are heated for 1% to 2 hours with stirring. To the cooled solution a solution of 4.2 grams of sodium hydroxide in 60 cc. of 95% ethanol is added slowly. Sodium-l-ascorbate precipitates and is filtered by suction.

' I claim:

1. The process of synthesizing compounds of the ascorbic acid series, which comprises sub- Jecting keto-acid esters of the general formula coo lower m1 0 dnon non ($808).

mil in which n represents 0, 1 or 2, and R is a member selected from the group consisting of H and OH, to the action of at least a molecular equivalent of a secondary amine selected from the group consisting of dicyclohexylamine, N-methyl-cycloheulamine, N-ethyl-cyclohexyiamine, N-propylcyclohexylamine. and .N-methyl-benzylamine.

2. The process of claim 1 in which the conversion is carried out at about 8040 C.

3. The process of claim 1 in which the amine is dicyclohexylamine.

4. The process of claim 1 in which the amine is N-ethyl-cyclohexylamine.

5. The process of claim 1 in which the ester is a methyl ester. Y

6. The process of claim 1 in which the ester is an ethyl ester.

7. The process of claim 1 in which the ester is m'ethyl-2-keto-l-gulonate.

8. The process of claim 1 in which the ester is methyi-2-keto-d-gluconate.

9.Theprocessof-elaim1 inwhichtheester is 1-methyl-2-keto-l-gulonate, and the amine is dicyclohexylamine.

10. Theprocessotclaimiinwhichtheester is 1-methyl-2-keto-d-gluconate, and the amine is dicyclohexylamine.

11. The process of claim 1 which includes treating the resulting amine salt of the ascorbic acid with sodium hydroxide to form the corresponding sodium ascorbate.

12. The process of claim 1 which includes treating the resulting amine salt of the ascorbic acid with 'sodium hydroxide to form the corresponding sodium ascorbate, and converting said salt to the corresponding free ascorbic acid by means of an acid agent.

13. The process of claim 1 which includes treating the resulting amine salt of the ascorbic acid with sodium hydroxide to form the corresponding sodium ascorbate, followed by conversion of said salt to the corresponding free ascorbic acid by means of hydrochloric acid.

14. The process of claim 1 in which the reaction is carried out in the presence of an alcoholic medium.

15. The process of claim 1 in which the reaction is carried out in ethanol and the resulting amine salt of the ascorbic acid is treated with sodium hydroxide to form the corresponding sodium ascorbate.

16. The process of forming an isoascorbic acid compound which comprises subjecting methyl-2- keto-d-gluconate in an alcohol medium to dicyclohexylamine to form the corresponding amine salt of isoascorbic acid. I

17. A process as in claim 16 in which the resulting amine salt is treated with sodium hydroxide to form the corresponding sodium isoascorbate.

16. The, process of producing l-ascorbic acid compounds which comprises subjecting 2-keto-lgulonic acid methylester to'dicyclohexylamine in an alcohol medium to form the corresponding amine salt of l-ascorbic acid.

19. A process as in claim 18 in which the resulting amine salt is treated with sodium hydroxide to form the corresponding l-sodium- 7 REFERENCES CITED The following references are of record in the ills of this patent:

UNITED STATES PATENTS Number Name Date 2,132,662 volwiler et a1. Oct. 11, 193s OTHER REFERENCES Maui-er et al.: Berichte, 1041, volume '14, pp. 1003, 1000. I 

